Aluminum-induced amyloidogenesis and impairment in the clearance of amyloid peptides from the central nervous system (cns) in Alzheimer's disease (AD)

Abstract

The membrane-integral beta amyloid precursor protein (βAPP) is probably the most intensively studied brain cell protein in all of neurobiology. βAPP is processed by tandem beta-gamma secretase cleavage into 42 amino acid amyloid (Aβ42) peptides whose progressive accumulation is one distinguishing feature of Alzheimer's disease (AD) neuropathology [1-3]. While homeostatic amounts of Aβ42 peptide generation and clearance seem to be tolerated by brain cells, their over-abundance, aggregation into higher order structures and inability of brain cells to effectively phagocytose and clear these intensely hydrophobic peptides contributes to the pro-inflammatory and neurotoxic pathology of AD. Aluminum, as an extremely high charge density cation (Z2/r=18) has the remarkable capability to both (1) aggregate and compact Aβ42 peptide monomers into higher order, more neurotoxic oligomeric and fibrillar structures, and (2) impair, at the molecular-genetic level, the cellular machinery responsible for Aβ42 peptide monomer phagocytosis and clearance from the cell [4-13]. This opinion paper will briefly assess these two remarkable, functionally overlapping, and decidedly neurotoxic properties of aluminum - (1) on the ability of physiologically realistic amounts of aluminum to aggregate Aβ42 peptide monomers into higher order dimeric, oligomeric and fibrillar structures, and (2) on the ability of aluminum to impair, at nanomolar concentrations and at the level of epigenetic regulation, microglial cell-mediated clearance mechanisms of Aβ42 peptides from the extracellular space of the brain and CNS. © 2014 Zhao, Hill, Bhattacharjee, Percy, Pogue and Lukiw.